Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes
Benbo Song, Donalyn Scheuner, David Ron, Subramaniam Pennathur, Randal J. Kaufman
Benbo Song, Donalyn Scheuner, David Ron, Subramaniam Pennathur, Randal J. Kaufman
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Research Article Metabolism

Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes

Abstract

The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic β cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in β cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop–/– mice had improved glycemic control and expanded β cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved β cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop–/– mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in β cells under conditions of increased insulin demand.

Authors

Benbo Song, Donalyn Scheuner, David Ron, Subramaniam Pennathur, Randal J. Kaufman

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Figure 4

Chop-null mutation increases proliferation and reduces apoptosis within the islets of Leprdb/db mice.

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Chop-null mutation increases proliferation and reduces apoptosis within...
(A) Apoptosis. TUNEL staining was performed, and the number of positive cells (arrows) was quantified; n = 2–4 mice per condition. Scale bar: 50 μm. (B) Proliferation. BrdU-positive cells within islet areas were detected by immunohistochemistry, and the darkly stained nuclei were quantified from microscope images. Scale bar: 20 μm. ***P < 0.001.